Dihomo-[gamma]-linolenic acid inhibits xenograft tumor growth in mice bearing shRNA-transfected HCA-7 cells targeting delta-5-desaturase

• Published in: BMC cancer Vol. 18; no. 1
• Main Authors: Xu, Yi, Yang, Xiaoyu, Gao, Di, Yang, Liu, Miskimins, Keith, Qian, Steven Y
• Format: Journal Article
• Language: English
• Published: BioMed Central Ltd 19.12.2018
• Subjects: Care and treatment; Colon cancer; Cyclooxygenases; Fatty acid desaturases; Genetic aspects; Health aspects; Laboratory rats; Xenotransplantation
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-018-5185-9

Background We previously demonstrated that knockdown of delta-5-desaturase via siRNA transfection together with dihomo-[gamma]-linolenic acid supplementation inhibited colon cancer cell growth and migration, by promoting the production of the anti-cancer byproduct 8-hydroxyoctanoic acid from Cyclooxygenase-2-catalyzed dihomo-[gamma]-linolenic acid peroxidation. Here, we extend our study to investigate the effects of delta-5-desaturase-knockdown and the resulting intensified dihomo-[gamma]-linolenic acid peroxidation in xenograft tumor mice model. Methods Four-week old nude mice bearing the human colon cancer cell HCA-7/C29 vs. its delta-5-desaturase knockdown analog (via shRNA transfection) were subject to 4-week treatments of: vehicle control, dihomo-[gamma]-linolenic acid supplementation, 5-Fluorouracil, and combination of dihomo-[gamma]-linolenic acid and 5-Fluorouracil. Tumor growth was monitored during the treatment. At the endpoint, the mice were euthanized and the tumor tissues were collected for further mechanism analysis. Results Delta-5-desaturase knockdown (shRNA) together with dihomo-[gamma]-linolenic acid supplementation increased 8-hydroxyoctanoic acid production to a threshold level in xenograft tumors, which consequently induced p53-dependent apoptosis and reduced tumors significantly. The promoted 8-hydroxyoctanoic acid formation was also found to suppress the tumors' metastatic potential via regulating MMP-2 and E-cadherin expressions. In addition, our in vivo data showed that delta-5-desaturase knockdown along with dihomo-[gamma]-linolenic acid supplementation resulted in anti-tumor effects comparable to those of 5-Fluorouracil. Conclusions We have demonstrated that our paradigm-shifting strategy of knocking down delta-5-desaturase and taking advantage of overexpressed Cyclooxygenase-2 in tumor cells can be used for colon cancer suppression. Our research outcome will lead us to develop a better and safer anti-cancer therapy for patients. Keywords: COX-2-catalyzed DGLA peroxidation, Knockdown of delta-5-desaturase, Xenograft tumor, Cancer growth and migration, HDAC inhibitor